pH/reduction dual-responsive hyaluronic acid-podophyllotoxin prodrug micelles for tumor targeted delivery

Polymer-based prodrug nanocarriers with tumor-targeting and controlled-release properties are in great demand for enhanced cancer treatment. Hyaluronic acid (HA), which has excellent biocompatibility and targeting ability for cluster determinant 44 (CD44), has been proposed for delivering drugs that have poor solubility and high toxicity. Herein, podophyllotoxin (PPT) was conjugated to HA via ester and disulfide linkages to construct a pH- and reduction-responsive prodrug (HA-S-S-PPT). The micelles self-assembled from HA-S-S-PPT prodrug efficiently accumulated at tumor site due to HA receptor-mediated endocytosis. HA-S-S-PPT micelles exhibited 33.1% higher cumulative release than HA-NH-CO-PPT micelles (sensitive only to pH) owing to their dual responsiveness to pH and reduction. HA-S-S-PPT micelles achieved excellent antitumor activity in vivo, with the tumor inhibition rate reaching 92%, significantly higher than that of HA-NH-CO-PPT micelles (65%), and negligible systemic toxicity. This controllable-targeting nanoparticle system provides a potential platform for clinical application of PPT.